Naphtho[1,2-d]thiazol-2-ylamine (SKA-31), a new activator of KCa2 and KCa3.1 potassium channels, potentiates the endothelium-derived hyperpolarizing factor response and lowers blood pressure

Ananthakrishnan Sankaranarayanan, Girija Raman, Christoph Busch, Tim Schultz, Pavel I. Zimin, Joachim Hoyer, Ralf Köhler, Heike Wulff

Research output: Contribution to journalArticle

141 Scopus citations

Abstract

Small-conductance (KCa2.1-2.3) and intermediate-conductance (KCa3.1) calcium-activated K + channels are critically involved in modulating calcium-signaling cascades and membrane potential in both excitable and nonexcitable cells. Activators of these channels constitute useful pharmacological tools and potential new drugs for the treatment of ataxia, epilepsy, and hypertension. Here, we used the neuroprotectant riluzole as a template for the design of KCa2/3 channel activators that are potent enough for in vivo studies. Of a library of 41 benzothiazoles, we identified 2 compounds, anthra[2,1-d] thiazol-2-ylamine (SKA-20) and naphtho[1,2-d] thiazol-2-ylamine (SKA-31), which are 10 to 20 times more potent than riluzole and activate KCa2.1 with EC 50 of 430 nM and 2.9 μM, KCa2.2 with an EC 50 value of 1.9 μM, KCa2.3 with EC 50 values of 1.2 and 2.9 μM, and KCa3.1 with EC 50 values of 115 and 260 nM. Likewise, SKA-20 and SKA-31 activated native KCa2.3 and KCa3.1 channels in murine endothelial cells, and the more "drug-like" SKA-31 (half-life of 12 h) potentiated endothelium-derived hyperpolarizing factor-mediated dilations of carotid arteries from KCa3.1(+/+) mice but not from KCa3.1(-/-) mice. Administration of 10 and 30 mg/kg SKA-31 lowered mean arterial blood pressure by 4 and 6 mm Hg in normotensive mice and by 12 mm Hg in angiotensin-II-induced hypertension. These effects were absent in KCa3.1-deficient mice. In conclusion, with SKA-31, we have designed a new pharmacological tool to define the functional role of the KCa2/3 channel activation in vivo. The blood pressure-lowering effect of SKA-31 suggests KCa3.1 channel activation as a new therapeutic principle for the treatment of hypertension.

Original languageEnglish (US)
Pages (from-to)281-295
Number of pages15
JournalMolecular Pharmacology
Volume75
Issue number2
DOIs
StatePublished - Feb 2009

ASJC Scopus subject areas

  • Pharmacology
  • Molecular Medicine

Fingerprint Dive into the research topics of 'Naphtho[1,2-d]thiazol-2-ylamine (SKA-31), a new activator of KCa2 and KCa3.1 potassium channels, potentiates the endothelium-derived hyperpolarizing factor response and lowers blood pressure'. Together they form a unique fingerprint.

  • Cite this